Paclitaxel With and Without Pazopanib for Persistent or Recurrent Ovarian Cancer: A Randomized Clinical Trial

Abstract

Importance: Ovarian cancer is the leading cause of gynecologic cancer deaths in the United States. Pazopanib is an oral, multitarget kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptors α and β; and proto-oncogene receptor tyrosine kinase (c-KIT).

Objective: To estimate the progression-free survival (PFS) hazard ratio (HR) of weekly paclitaxel and pazopanib compared with weekly paclitaxel and placebo in women with recurrent ovarian cancer. Secondary objectives included frequency and severity of adverse events, proportion responding, and overall survival (OS) in each arm. Translational research objectives included exploring the association between possible biomarkers and single-nucleotide polymorphisms in vascular endothelial growth factor A, interleukin 8, and hypoxia-inducible factor 1α; and PFS, OS, and proportion responding.

Design, setting, and participants: A randomized, placebo-controlled, double-blind phase 2 study was conducted at 26 participating institutions. Patients were enrolled between December 12, 2011, and April 22, 2013. Data were frozen on August 11, 2014. Participants were patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with 1 to 3 prior regimens and performance status of 0 to 2. One hundred six patients enrolled; 100 were evaluable for toxic effects.

Interventions: All patients received paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 every 28 days and were randomized 1:1 to pazopanib 800 mg orally daily or placebo.

Main outcomes and measures: The primary end point was PFS. The study was designed to detect a 37.5% reduction in the hazard with 80% power (α = 10%).

Results: A total of 106 women (median age [range], 61 [35-87] years; 88 [83%] white) were enrolled. Study arms were well balanced for age, performance status, measurable disease, and prior bevacizumab. Proportion responding was 14 of 44 (31.8%) vs 10 of 44 (22.7%) for pazopanib plus paclitaxel vs paclitaxel alone. Median PFS was 7.5 vs 6.2 months for pazopanib plus paclitaxel vs paclitaxel alone, respectively (HR, 0.84; 90% CI, 0.57-1.22; P = .20). Median OS was 20.7 vs 23.3 months for pazopanib plus paclitaxel vs paclitaxel alone (HR, 1.04; 90% CI, 0.60-1.79; P = .90). Severe hypertension was more common on the pazopanib plus paclitaxel arm (relative risk, 12.0; 95% CI, 1.62-88.84). More patients discontinued treatment on the paclitaxel arm for disease progression (34 of 52 [65.4%] vs 17 of 54 [31.5%]), and more on the pazopanib plus paclitaxel arm for adverse events (20 of 54 [37%] vs 5 of 52 [9.6%]). No association was found between single-nucleotide polymorphisms (interleukin 8 and hypoxia-inducible factor 1α) and OS and proportion responding. Patients with VEGFA CC genotype may be more resistant to weekly paclitaxel than those with the AC or AA genotype, with 1 of 14 (7%), 3 of 15 (20%), and 4 of 8 (50%) responding, respectively.

Conclusions and relevance: The combination of pazopanib plus paclitaxel is not superior to paclitaxel in women with recurrent ovarian cancer.

Trial registration: clinicaltrials.gov Identifier: NCT01468909.

Figure 1.. CONSORT Diagram

Of 106 women enrolled, 52 were randomized to the placebo arm and 54 to the pazopanib arm. The researchers then compared efficacy and toxic effects of pazopanib vs placebo.

Figure 2.. Progression-Free Survival by Study Regimen

Progression-free survival was not statistically different between the pazopanib and placebo groups. Median progression-free survival was 7.5 months (90% CI, 5.5-9.0) on the pazopanib arm compared with 6.2 months (90% CI, 5.6-8.3) on the placebo arm. Exp indicates experimental regimen; ref, reference regimen.

Figure 3.. Overall Survival by Study Regimen

There was no difference in overall survival between the 2 groups. Median overall survival was 20.7 months (90% CI, 17.0-22.6) in the pazopanib arm vs 23.3 months (17.3-not reached) in the placebo arm. Exp indicates experimental regimen; ref, reference regimen.